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Section on Endocrinology and Genetics, Pediatric Endocrinology Inter‐institute Training Program Building 10, Molecular Neurophysiology and Biophysics Unit, Endocrine Oncology Section, Program on Developmental Endocrinology and Genetics (PDEGEN)
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KCNJ5 mutations were recently described in primary hyperaldosteronism (PH or Conn's syndrome). The frequency of these mutations in PH and the way KCNJ5 defects cause disease remain unknown. A total of 53 patients with PH have been seen at the National Institutes of Health over the last 12 years. Their peripheral and tumor DNAs (the latter from 16 that were operated) were screened for KCNJ5 mutations; functional studies on the identified defects were performed after transient transfection. Only two mutations were identified, and both in the tumor DNA only. There were no germline sequencing defects in any of the patients except for known synonymous variants of the KCNJ5 gene. One mutation was the previously described c.G451C alteration; the other was a novel one in the same codon: c.G451A; both lead to the same amino acid substitution (G151R) in the KCNJ5 protein. Functional studies confirmed previous findings that both mutations caused loss of channel selectivity and a positive shift in the reversal potential. In conclusion, the KCNJ5 protein was strongly expressed in the zona glomerulosa of normal adrenal glands but showed variable expression in the aldosterone-producing adenomas with and without mutation. The rate of KCNJ5 mutations among patients with PH and/or their tumors is substantially lower than what was previously reported. The G151R amino acid substitution appears to be the most frequent one so far detected in PH, despite additional nucleotide changes. The mutation causes loss of this potassium channel's selectivity and may assist in the design of new therapies for PH.
Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA
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Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA
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Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA
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Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA
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Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA
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IGSF1 is a membrane glycoprotein highly expressed in the anterior pituitary. Pathogenic mutations in the IGSF1 gene (on Xq26.2) are associated with X-linked central hypothyroidism and testicular enlargement in males. In this study, we tested the hypothesis that IGSF1 is involved in the development of pituitary tumors, especially those that produce growth hormone (GH). IGSF1 was sequenced in 21 patients with gigantism or acromegaly and 92 healthy individuals. Expression studies with a candidate pathogenic IGSF1 variant were carried out in transfected cells and immunohistochemistry for IGSF1 was performed in the sections of GH-producing adenomas, familial somatomammotroph hyperplasia, and in normal pituitary. We identified the sequence variant p.N604T, which in silico analysis suggested could affect IGSF1 function, in two male patients and one female with somatomammotroph hyperplasia from the same family. Of 60 female controls, two carried the same variant and seven were heterozygous for other variants. Immunohistochemistry showed increased IGSF1 staining in the GH-producing tumor from the patient with the IGSF1 p.N604T variant compared with a GH-producing adenoma from a patient negative for any IGSF1 variants and with normal control pituitary tissue. The IGSF1 gene appears polymorphic in the general population. A potentially pathogenic variant identified in the germline of three patients with gigantism from the same family (segregating with the disease) was also detected in two healthy female controls. Variations in IGSF1 expression in pituitary tissue in patients with or without IGSF1 germline mutations point to the need for further studies of IGSF1 action in pituitary adenoma formation.